Written in Blood
Predicting MDS and AML Before it Begins
Targeted Sequencing Identifies Patients at High Risk for Disease Development
The diagnosis of myelodysplastic
syndromes (MDS) remains difficult
due to the subjective nature of
morphologic assessment and the
heterogeneity of the disease itself,
but a new report published in Blood
finds that, in patients who don’t yet
have morphologic evidence of MDS
or AML, certain mutations can
predict those patients at high risk
for developing the disease.
In this retrospective study, Catherine Cargo, MB, from the Hematological Malignancy Diagnostic
Service at St. James’ University
“Early detection would
provide an
increased
window for
therapeutic
intervention
in those with
very poor
prognosis.”
—CATHERINE CARGO, MB
38
ASH Clinical News
Hospital in the United Kingdom,
and colleagues sought to molecularly characterize those patients with
suspected MDS who have failed to
meet strict diagnostic criteria using
conventional techniques.
While cytogenetics can provide
objective evidence of disease, this
approach has been complicated
by reports of frequent somatic
mutations and large chromosomal
abnormalities in healthy patients.
Therefore, the authors stated,
“[Patients] with clinically significant
mutations are currently indistinguishable from those who will not
progress.” Dr. Cargo and co-authors
hypothesized that analyzing the
molecular abnormalities in these
patients would provide potential
criteria to distinguish pre-clinical
MDS from healthy individuals and
detect those patients at high risk for
developing the disease.
The researchers identified 82
patients from the Hematological
Malignancy Diagnostic Service
between 2004 and 2012 who,
despite having an initial bone
marrow with non-diagnostic features, went on to develop progressive dysplasia or acute myeloid
leukemia (AML). They were
compared with a cohort of healthy
patients from several published
studies reporting on clonal hematopoiesis. Sixty-nine patients had
adequate molecular material at
both pre-diagnostic and diagnostic timepoints, and 59 patients had
survival data available.
To investigate the impact of
genetic abnormalities on overall
survival (OS) and the association
between genetic mutations and
disease development, the researchers performed targeted sequencing
for 26 commonly mutated genes in
myeloid malignancies and arraybased analyses on patient samples.
Most patients (63 patients;
91%) had a driver mutation and/or
structural variant on pre-diagnostic
samples, including 133 mutations
among 62 patients, most commonly involving epigenetic regulators
or spliceosome genes. At this point,
the researchers noted, the spectrum of mutations mirrored the
mutations reported in large MDS
populations, with TET2 mutated in
39 percent of patients, SRSF2 in 26
percent, and ASXL1 in 20 percent.
DNMT3A was the most frequently
mutated gene in the healthy population, though this was only seen in
10 percent of this patient cohort.
A median of two mutations
were detected per patient (range =
1-5), and the frequency of multiple
mutations was greater in the AML/
MDS patient population compared
with the healthy cohort (64% vs.
0.8%; p value not reported).
Of the 59 patients with OS data
available, only 10 remained alive at
the point of analysis. “Median OS
from the pre-diagnostic sample was
43.6 months (95% CI 33.8-55.8)
and, as expected, much shorter
from diagnosis (13 months; 95%
CI 9.9-24.6),” Dr. Vaughn and colleagues reported. Patients diagnosed
with AML had a median OS of 1.28
months (95% CI 0.789-12.625).
Thirty-nine patients progressed
to refractory anemia with excess
blasts (RAEB) or AML and, notably, this occurred in a significantly
shorter time than progression to
refractory cytopenia with multilineage dysplasia (median = 403 vs.
606 days; HR=3.7 95% CI 2.1-6.6;
p<0.001). Analysis of the most
frequently mutated genes revealed
that IDH2 and TP53 mutations
were associated with a more
rapid time to disease progression
(HR=4.2; 95% CI 1.3-13.8; p=0.017
for IDH2 and HR=5.5; 95% CI 1.127.7; p=0.038 for TP53).
Certain pre-diagnostic mutations were also associated with
significantly worse OS, particularly
for TP53 (hazard ratio [HR] =
21.68; 95% CI 4.72-99.64; p<0.001)
and U2AF1 (HR=2.63; 95% CI 1.06.4; p=0.049).
Thirty patients (43%) acquired
a mutation between pre-diagnostic and diagnostic samples, most
commonly involving transcription
factors and cell-signaling genes.
These mutations also correlated
strongly with progression to RAEB
and AML.
“The mutational profile in our
cohort differs significantly from
that in the healthy population
and has the potential to identify
patients with clonal hematopoiesis of indeterminate potential or
clonal cytopenias of undetermined
significance who are at greater risk
of progression, even in the absence
of morphological disease,” Dr.
Vaughn and co-authors concluded.
“Early detection would provide an
increased window for therapeutic
intervention in those with very
poor prognosis.”
However, the diagnostic utility
of these findings is limited by the
lack of a control group of patients
who did not progress to AML/
MDS. “Our study design included
only those patients re-investigated
for cytopenia and both the mutation and disease frequency is likely
to be greater,” the authors wrote,
suggesting that the optimal way to
explore this and refine molecular
criteria for diagnosis is to prospectively study an unselected cytopenic
patient cohort. A study like this is
currently underway, they added. ●
REFERENCE
Cargo CA, Rowbotham N, Evans PA, et al. Targeted
sequencing identifies patients with pre-clinical MDS at
high risk of disease progression. Blood. 2015 September 17.
[Epub ahead of print]
November 2015